miRNAs as therapeutic targets in cancer

Abstract

MicroRNAs (miRNAs) are a class of non-coding small RNA molecules that regulate gene expression at the post-transcriptional level by interacting with 3′ untranslated regions (UTRs) of their target mRNAs. The invention relates to the application of miR-192 and miR-215. Both of these miRNAs impact cellular proliferation through the p53-miRNA circuit, and interact with dihydrofolate reductase (DHFR) and thymidylate synthase (TS). Particularly, upregulation of these miRNAs reduces cellular proliferation. The invention relates to this discovery. For example, inhibiting miR-192 and/or miR-215 sensitizes a neoplasm or a subject with a neoplasm to chemotherapeutic agents. Furthermore, measuring the levels of miR-192 and/or miR-215 provides one with information regarding whether the neoplasm or subject will respond to chemotherapeutic agents. Accordingly, the invention relates to composition and methods relating to the identification, characterization and modulation of the expression of miR-192 and miR-215.

What is claimed is: 
     
       1. A method of increasing sensitivity of a cell to a chemotherapeutic agent, comprising contacting the cell with a nucleic acid selected from the group consisting of a complimentary sequence to SEQ ID NOs:1, 2, 3, 9, 10 and 25 or having a sequence of SEQ ID NO:25, in an amount effective to sensitize the cell to the chemotherapeutic agent, wherein the sensitivity of the cell to the chemotherapeutic agent is increased, and contacting the cell with the chemotherapeutic agent. 
     
     
       2. The method of  claim 1 , wherein the chemotherapeutic agent is selected from methotrexate, fluorouracil (5-FU), and ralitrexed. 
     
     
       3. The method of  claim 1 , wherein the nucleic acid is an antisense nucleic acid. 
     
     
       4. The method of  claim 1 , wherein the nucleic acid is an siRNA or an shRNA. 
     
     
       5. The method of  claim 1 , wherein the cell is a cancer stem cell. 
     
     
       6. The method of  claim 1 , wherein the cell is a neoplastic cell.